The Eicosanoids
Metabolites of arachidonic acid and related fatty acids exhibit a wide range of biological activities affecting every organ system in the body. There are over thirty metabolites of arachidonic acid which exhibit biological activity. These metabolites are collectively termed eicosanoids.
Arachidonic acid is stored in the cell esterified to membrane lipids. Once released from membrane lipids, arachidonic acid may either be re-esterified back into membrane lipids or metabolized via a variety of oxidative enzymes. There are two oxidative pathways which are of importance for therapeutic intervention; the cyclo-oxygenase pathway which generates prostaglandins, thromboxanes and prostacyclin, and the lipoxygenase pathway which generates leukotrienes, lipoxins, hydroperoxyeicosatetraenoic acids and the mono- and di-hydroxyeicosatetraenoic acids (mono- and di-HETE's). (See FIG. 1). Although platelet activating factor (PAF) is not a direct metabolite of arachidonic acid, it is generated through one of the pathways which generate free arachidonic acid. Thus, in some cases, generation of free arachidonic acid also results in the generation of lyso-PAF, a direct precursor for PAF.
Prostaglandins of the E series (PGE.sub.1, PGE.sub.2) are potent vasodilators and smooth muscle relaxants. Thus, PGE.sub.2 promotes hypotension and relaxes bronchial, tracheal and uterine smooth muscle. Other effects of these prostaglandins include inhibition of platelet aggregation, inhibition of mediator release from mast cells, increased renal blood flow, diuresis, increased circulating concentrations of ACTH, and inhibition of gastric acid secretion. PGEs cause pain when injected intradermally and sensitize afferent nerve endings to the effects of chemicals or mechanical stimuli.
Prostaglandin D2, like PGE1, is an inhibitor of platelet aggregation. PGD2 enhances the release of histamine from basophils, promotes chemokinesis and enhances the chemotactic response of other mediators in polymorpholeukocytes. Prostacyclin (PGI.sub.2) is a potent vasodilatory substance and, general smooth muscle relaxant. PGI.sub.2 is 30 to 50 times more potent than PGE2 and PGD2 in inhibiting platelet aggregation. PGI2 inhibits gastric acid secretion, relaxes bronchial and uterine smooth muscle, and increases renal blood flow. Thus, PGE2, PGI2, and, to a lesser extent PGD2, are important in maintaining normal homeostasis and have beneficial effects in many clinical situations.
Prostaglandins of the F series, i.e., PGF2.alpha., in general exhibit biological activity opposite to PGE on smooth muscle tissue. PGF2.alpha. contracts bronchial and tracheal smooth muscle, contracts both pregnant and nonpregnant uterine smooth muscle, and contracts gastrointestinal smooth muscle. In subprimates PGF2.alpha. is the leutolytic hormone.
Thromboxane A.sub.2 (TXA.sub.2) is a potent smooth muscle contractile agent, contracting all smooth muscle strips tested including vasculature, bronchial, and tracheal. TXA.sub.2 promotes platelet aggregation and decreases renal blood flow.
In general, the peptidoleukotrienes (leukotrienes C.sub.4, D.sub.4, and E.sub.4) are potent smooth muscle contractile agents, while leukotriene B.sub.4 (LTB4) is a chemotactic factor for circulating neutrophils and monocytes. LTB.sub.4 also promotes lysosomal enzyme release and superoxide anion generation from neutrophils, both of which cause local tissue damage (Ford-Hutchinson, A. W., Crit. Rev. in Immunol., 10:1-12, 1989). Lipoxins have been shown to contract guinea pig parenchymal strips, inhibit natural killer cells, and to stimulate superoxide generation in neutrophils.
Platelet activating factor (PAF) induces platelet aggregation, increases vascular permeability, acts as a bronchoconstrictor, decreases renal blood flow, decreases mesenteric circulation, and is the most potent gastric ulcerogen yet described (Rosam et al., Nature, 319: 54-56, 1986). PAF activates inflammatory cells promoting neutrophil and eosinophil chemotaxis and degranulation (Braquet et al., ISI Atlas of Science: Pharmacology, 187-198, 1987).